REVIEW

Pirfenidone in Idiopathic Pulmonary Fibrosis: ExpertPanel Discussion on the Management of Drug-RelatedAdverse Events

Ulrich Costabel • Elisabeth Bendstrup • Vincent Cottin • Pieter Dewint • Jim J. J. Egan •

James Ferguson • Richard Groves • Per M. Hellstrom • Michael Kreuter • Toby M. Maher •

Maria Molina-Molina • Klas Nordlind • Alexandre Sarafidis • Carlo Vancheri

To view enhanced content go to www.advancesintherapy.comReceived: January 15, 2014 / Published online: March 18, 2014� The Author(s) 2014. This article is published with open access at Springerlink.com

ABSTRACT

Pirfenidone is currently the only approved

therapy for idiopathic pulmonary fibrosis,

following studies demonstrating that treatment

reduces the decline in lung function and

improves progression-free survival. Although

generally well tolerated, a minority of patients

discontinue therapy due to gastrointestinal and

skin-related adverse events (AEs). This review

summarizes recommendations based on existing

guidelines, research evidence, and consensus

opinions of expert authors, with the aim of

providing practicing physicians with the specific

clinical information needed to educate the

patient and better manage pirfenidone-related

AEs with continued pirfenidone treatment. The

main recommendations to help prevent and/or

mitigate gastrointestinal and skin-related AEs

include taking pirfenidone during (or after) a

meal, avoiding sun exposure, wearing protective

clothing, and applying a broad-spectrum

Electronic supplementary material The onlineversion of this article (doi:10.1007/s12325-014-0112-1)contains supplementary material, which is available toauthorized users.

U. Costabel (&)Department of Pneumology/Allergology,Ruhrlandklinik, University Hospital, UniversityDuisburg-Essen, Essen, Germanye-mail: ulrich.costabel@ruhrlandklinik.uk-essen.de

E. BendstrupDepartment of Respiratory Medicine andAllergology, Aarhus University Hospital, Aarhus,Denmark

V. CottinHopital Louis Pradel, Service de Pneumologie,Centre de Reference National des MaladiesPulmonaires Rares, Universite Claude BernardLyon 1, UMR754, Lyon, France

P. DewintDepartment of Gastroenterology and Hepatology,Erasmus Medical Center, Rotterdam,The Netherlands

J. J. J. EganDepartment of Respiratory Medicine, MaterMisericordiae University Hospital, Dublin, Ireland

J. FergusonDepartment of Dermatology, Ninewells Hospital,Dundee, UK

R. GrovesDivision of Genetics and Molecular Medicine,St. John’s Institute of Dermatology, King’s CollegeLondon School of Medicine, London, UK

P. M. HellstromDepartment of Medical Sciences, Gastroenterologyand Hepatology, Uppsala University, Uppsala,Sweden

Adv Ther (2014) 31:375–391

DOI 10.1007/s12325-014-0112-1

sunscreen with high ultraviolet (UV) A and UVB

protection. These measures can help optimize AE

management, which is key to maintaining

patients on an optimal treatment dose.

Keywords: Adverse event management; Expert

opinion; Gastrointestinal events; Idiopathic

pulmonary fibrosis; Photosensitivity;

Pirfenidone; Respiratory; Safety; Skin-related

events

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF) is a rare,

progressive, irreversible and ultimately fatal

chronic lung disease. Studies in Europe suggest

that prevalence ranges from 1 to 23 cases per

100,000 persons [1–6]. Prevalence and

incidence rates increase with age, are higher

among males and appear to be on the increase

in recent years [7]. Prognosis is poor, with a

median survival time of 2–5 years [8–12].

Pirfenidone is currently the only approved

drug for the treatment of adult patients with

mild to moderate IPF [13]. It is licensed for use

in the European Union and Canada (under the

trade name Esbriet�, InterMune UK Ltd.,

London, UK) and in Japan, India, South Korea,

and China. Data from Phase III, randomized,

double-blind, placebo-controlled trials

demonstrate that pirfenidone reduces the

decline in lung function and improves

progression-free survival time [14, 15]. In these

studies, treatment with pirfenidone was safe

and generally well tolerated; the most

commonly reported treatment-emergent

adverse events (AEs) were gastrointestinal (GI)

and skin-related. These were generally mild to

moderate in severity and rarely resulted in

treatment discontinuation.

While pirfenidone is generally well tolerated,

a minority of patients discontinue treatment

due to AEs. In light of the vital importance of

treatment compliance in patients with IPF, a

clinical advisory board comprising experts in

pulmonology (E. Bendstrup, U. Costabel, V.

Cottin, J. J. J. Egan, M. Kreuter, T. Maher, M.

Molina-Molina, C. Vancheri), gastroenterology

(P. Dewint, P.M. Hellstrom, A. Sarafidis), and

dermatology (J. Ferguson, R. Groves, K.

Nordlind), and supported by a grant from

InterMune International AG, was convened in

Basel, Switzerland, to discuss the prevention

and management of pirfenidone-related GI and

skin-related AEs.

This review summarizes the

recommendations that have been generated

based on existing guidelines, a review of current

research evidence, and consensus opinions of

this international group of experts. The

recommendations may be adapted for use in

M. KreuterPneumology and Respiratory Critical CareMedicine, Thoraxklinik, University of Heidelbergand Translational Lung Research Centre Heidelberg,Heidelberg, Germany

T. M. MaherInterstitial Lung Disease Unit, Royal BromptonHospital, London, UK

M. Molina-MolinaUnidad Funcional de Intersticio Pulmonar, Serviciode Neumologıa, Hospital Universitario de Bellvitge,IDIBELL, CIBERES, Hospitalet de Llobregat,Barcelona, Spain

K. NordlindDermatology and Venerology Unit, Department ofMedicine, Solna, Karolinska University Hospital,Stockholm, Sweden

A. SarafidisDepartment of Gastroenterology, Parc LeopoldHospital (CHIREC), Brussels, Belgium

C. VancheriRegional Centre for Rare Lung Disease, University ofCatania, Catania, Italy

376 Adv Ther (2014) 31:375–391

different countries or regions according to the

availability of treatment modalities and treating

physicians’ judgment. The experts’ meeting

aimed to provide practicing physicians with

specific clinical information needed to best

educate the patient and manage AEs with

continued pirfenidone treatment. These

recommendations will be revised regularly

following systematic review of new research

evidence as it becomes available.

The analysis in this article is based on

previously conducted studies, and does not

involve any new studies of human or animal

subjects performed by any of the authors.

OVERVIEW OF PIRFENIDONE

Pirfenidone is an orally active, synthetic small

molecule that inhibits the synthesis of

transforming growth factor-b and tumor

necrosis factor-a in preclinical models, both of

which are cytokines known to play an active

role in fibrosis and inflammation [16–21].

Following oral administration with food to

improve tolerability, pirfenidone is slowly

absorbed and reaches peak concentrations

after approximately 4 h [22]. The mean

apparent terminal elimination half-life is

approximately 2.4 h [23].

Efficacy Profile

The clinical efficacy and safety of pirfenidone

has been evaluated in four randomized,

double-blind, placebo-controlled trials,

including a Phase II Japanese study, a Phase III

Japanese study, and two multinational Phase III

trials [the CAPACITY studies PIPF004

(Clinicaltrials.gov #NCT00287716) and PIPF006

(Clinicaltrials.gov #NCT00287729)] conducted

in Europe, North America and Australia [14, 15,

24]. Data from the three Phase III, randomized,

double-blind, placebo-controlled studies

demonstrate that pirfenidone reduces the

decline in lung function and improves

progression-free survival [14, 15]. The two

Phase III CAPACITY studies of pirfenidone in

patients with IPF were designed similarly in order

to enable pooling of data [25]. Analyses of pooled

data from both trials enabled precise estimates of

the magnitude of the treatment effect [25].

Results from the pooled analysis of categorical

FVC change showed that pirfenidone reduced

the proportion of patients experiencing at least a

10% decline by 30% compared with placebo [15].

Additionally, numerically fewer overall deaths

occurred in the pirfenidone versus placebo group

[19 (6%) vs. 29 (8%); P = 0.141]. Significant and

clinically meaningful treatment effects were

observed across multiple outcomes in the

CAPACITY studies (Fig. 1a) [26]. At Week 72,

pirfenidone also reduced the proportion of

patients with a 50 m or greater decrement in

6-min walk distance (31% relative reduction vs.

placebo) and reduced the risk of death or disease

progression (26% reduction vs. placebo,

P = 0.025) [15].

Safety Profile

The clinical safety profile of pirfenidone in

patients with IPF has been demonstrated

in large randomized, double-blind,

placebo-controlled trials [14, 15, 24], as well as

in an ongoing long-term open-label extension

trial [RECAP (Clinicaltrials.gov #NCT00662038)].

Pirfenidone’s safety profile has been evaluated in

a well-defined cohort of 789 patients exposed to

treatment for up to 8 years (long-term safety

pooling) [27]. In the CAPACITY studies,

treatment with pirfenidone was generally well

tolerated. Treatment discontinuation due to AEs

was more common among pirfenidone

Adv Ther (2014) 31:375–391 377

2,403 mg/day patients (15%) compared with

placebo patients (9%); relative risk of 1.85 (95%

CI 1.28–2.67, P = 0.001) [15, 28].

Based on observations from the Japanese

trials [14, 24], proactive protocol-defined

strategies including dose modification

378 Adv Ther (2014) 31:375–391

guidelines were implemented in the CAPACITY

studies to minimize the incidence and severity

of selected AEs (such as GI and skin-related AEs)

and encourage patients to continue treatment.

The most common AE leading to treatment

discontinuation in both groups in the

CAPACITY studies was IPF (3% in each group).

Other AEs leading to treatment discontinuation

in at least 1% of pirfenidone-treated patients

were rash and nausea.

The relatively low incidence of treatment

discontinuation due to GI and skin-related AEs

in the CAPACITY studies, compared with

the Japanese studies, supports the use of

protocol-defined strategies for proactively

managing these events. However, GI and

skin-related AEs remained the most

commonly reported AEs in the CAPACITY

studies. Gastrointestinal events of nausea,

diarrhea, dyspepsia and vomiting were

reported in 36%, 29%, 19% and 14% of

pirfenidone-treated patients versus 17%, 19%,

7%, and 4% of placebo-treated patients,

respectively [15] (InterMune data on file).

Skin-related AEs of rash and photosensitivity

were reported in 32% and 12% of

pirfenidone-treated patients versus 12% and

2% of placebo-treated patients, respectively

[15]. These events were generally mild to

moderate in intensity, reversible, and with

minimal clinical consequence (Tables 1, 2).

Gastrointestinal and skin-related AEs led to

treatment discontinuation in six (1.7%) and

eight (2.3%) pirfenidone-treated patients,

respectively. The long-term safety pooling

including 789 patients showed that GI and

skin-related AEs have a tendency to occur early

in the course of treatment and decrease over

time [27].

Elevations in alanine aminotransferase (ALT)

and aspartate aminotransferase (AST) of more

than three times the upper limit of normal

occurred more frequently in the pooled

pirfenidone group than in the pooled placebo

group [14/345 (4%) vs. 2/347 (\1%),

respectively] in the CAPACITY studies [15].

Rarely, these have been associated with

concomitant elevations in bilirubin. Liver

function tests (ALT, AST, and bilirubin) should

be conducted prior to the initiation of treatment

with pirfenidone, and subsequently at monthly

intervals for the first 6 months and then every

3 months thereafter [23].

Gastrointestinal Adverse Events

Gastrointestinal AEs occurred at higher

frequencies in patients treated with

pirfenidone 2,403 mg/day compared with

placebo in the CAPACITY studies (Table 1).

Importantly, there were no GI-related

treatment-emergent serious AEs or

hospitalizations among patients treated with

pirfenidone. Overall, five (1.4%) and one (0.3%)

pirfenidone patients discontinued therapy due

Fig. 1 Clinical and preclinical pirfenidone data.a Consistent magnitude of treatment effect withpirfenidone across multiple clinically meaningful outcomesin patients with IPF [15]. Bars represent the magnitude oftreatment effect, reported as relative difference between thepirfenidone and placebo groups. *From the pooled analysisof the CAPACITY studies at 72 weeks. �Progression-freesurvival was defined as time to confirmed C10% decline inpercentage predicted FVC, C15% decline in percentagepredicted DLco or death. Deaths were not adjudicated andstudies were not powered to evaluate mortality. b Theincidence of pirfenidone-related skin rashes in patientswith IPF was higher in the early summer months of theCAPACITY studies 004 and 006. Adapted fromEuropean Medicine Agency. Pirfenidone CHMPassessment report [38]. c Pirfenidone absorbs light in theultraviolet spectrum. Adapted from Seto et al. [30].6MWD 6-min walk distance, DLco carbon monoxidediffusing capacity, e molar absorptivity coefficient, FVCforced vital capacity, IPF idiopathic pulmonary fibrosis,kmax wavelength of the most intense ultraviolet absorption,PBO placebo, PEY patient-exposed years, PFDpirfenidone, PFS progression-free survival, UV ultraviolet

b

Adv Ther (2014) 31:375–391 379

Tab

le1

Gas

troi

ntes

tina

lad

vers

eev

ents

inth

eC

APA

CIT

Yst

udie

s

Nau

sea

Dia

rrhe

aD

yspe

psia

Vom

itin

g

Pir

feni

done

2,40

3m

g/da

y(N

534

5)

Pla

cebo

(N5

347)

Pir

feni

done

2,40

3m

g/da

y(N

534

5)

Pla

cebo

(N5

347)

Pir

feni

done

2,40

3m

g/da

y(N

534

5)

Pla

cebo

(N5

347)

Pir

feni

done

2,40

3m

g/da

y(N

534

5)

Pla

cebo

(N5

347)

Gra

de3

or4

TE

AE

s,n

(%)

6(1

.7)

2(0

.6)

2(0

.6)

0(0

.0)

1(0

.3)

2(0

.6)

1(0

.3)

0(0

.0)

TE

SAE

,n(%

)0

(0.0

)0

(0.0

)0

(0.0

)1

(0.3

)0

(0.0

)0

(0.0

)0

(0.0

)0

(0.0

)

Dea

ths,

n0

00

00

00

0

Hos

pita

lizat

ions

,n(%

)0

(0.0

)0

(0.0

)0

(0.0

)1

(0.3

)0

(0.0

)0

(0.0

)0

(0.0

)0

(0.0

)

Dis

cont

inua

tion

,n(%

)5

(1.4

)0

(0.0

)0

(0.0

)2

(0.6

)0

(0.0

)0

(0.0

)1

(0.3

)0

(0.0

)

Dos

em

odifi

cati

on,n

(%)

25(7

.2)

7(2

.0)

18(5

.2)

4(1

.2)

8(2

.3)

0(0

.0)

14(4

.1)

3(0

.9)

Eve

nts,

n19

577

153

8577

2962

17

Med

ian

dura

tion

,day

s46

77

516

84

23

Res

olve

d,n

(%)

149

(76)

65(8

4)13

0(8

5)73

(52)

40(5

2)23

(79)

59(9

5)17

(100

)

TE

AE

trea

tmen

t-em

erge

ntad

vers

eev

ent,

TE

SAE

trea

tmen

t-em

erge

ntse

vere

adve

rse

even

t,G

rade

3T

EA

Ese

vere

orm

edic

ally

sign

ifica

ntbu

tno

tim

med

iate

lylif

e-th

reat

enin

gev

ents

;ho

spit

aliz

atio

nor

prol

onga

tion

ofho

spit

aliz

atio

nin

dica

ted;

disa

blin

g;lim

itin

gse

lf-ca

reA

ctiv

itie

sof

Dai

lyL

ivin

g,G

rade

4T

EA

Elif

e-th

reat

enin

gco

nseq

uenc

es;

urge

ntin

terv

enti

onin

dica

ted.

Inte

rMun

eda

taon

file

380 Adv Ther (2014) 31:375–391

to nausea and vomiting, respectively, and two

(0.6%) discontinued due to diarrhea.

Gastrointestinal AEs were mostly transient in

nature, although dyspepsia was present for a

median duration of 168 days [15]. While

GI-related AEs were generally mild to moderate

and transient, the frequency of such events

suggests the need for proactive management.

Animal studies have shown that pirfenidone

reduces the rate of gastric emptying and small

intestinal transit [29]. These effects in rats were

ameliorated by co-administration of prokinetic

agents. Concomitant administration of

mosapride at 3 and 10 mg/kg resulted in

significant amelioration in the decrease in

gastric emptying rate induced by 100 mg/kg

pirfenidone, while 1 mg/kg mosapride or greater

ameliorated the decreased small intestinal

transit rate [29]. Furthermore, GI effects in

animals were observed following subcutaneous

injection, indicating that systemic exposure is

required for pirfenidone’s gastric motility effects

(InterMune data on file). The effect of food

on the pharmacokinetics of pirfenidone

has previously been examined in healthy

adult subjects. It was demonstrated that

co-administration with food decreased the peak

concentration of pirfenidone (area under the

curve was unchanged), with data also suggesting

that food intake reduces the risk of GI-related AEs,

thereby improving overall tolerability [22].

Skin Reactions

Skin-related AEs in the context of pirfenidone

therapy can manifest as an erythematous (with/

without edema) or as a phototoxic burn-like

skin rash, occurring on sun-exposed body areas.

This differs from an allergic type of eruption,

which will usually affect all parts of the skin,

including areas not exposed to sunlight. In the

Table 2 Skin-related adverse events in the CAPACITY studies

Rash Photosensitivity reaction

Pirfenidone 2,403 mg/day(N 5 345)

Placebo(N 5 347)

Pirfenidone 2,403 mg/day(N 5 345)

Placebo(N 5 347)

Grade 3 or 4 TEAEs, n (%) 2 (0.6) 0 (0.0) 3 (0.9) 1 (0.3)

TE SAEs, n (%) 1 (0.3)a 0 (0.0) 1 (0.3) 0 (0.0)

Deaths (n) 0 0 0 0

Hospitalization, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Discontinuation, n (%) 5 (1.4) 0 (0.0) 3 (0.9) 1 (0.3)

Dose modification, n (%) 42 (12.2) 5 (1.5) 19 (5.5) 1 (0.3)

Events (n) 159 52 60 8

Median duration (days) 38 31 88 60

Resolved, n (%) 132 (83) 46 (88) 47 (78) 6 (75)

No formal definition of rash versus photosensitivity reaction was employed; the distinction was made by the physician basedon his/her clinical observationTEAE treatment-emergent adverse event, TE SAE treatment-emergent severe adverse event, Grade 3 TEAE severe ormedically significant but not immediately life-threatening events; hospitalization or prolongation of hospitalizationindicated; disabling; limiting self-care Activities of Daily Living, Grade 4 TEAE life-threatening consequences; urgentintervention indicated. InterMune data on filea Grade 3 erythema with desquamation

Adv Ther (2014) 31:375–391 381

CAPACITY studies, the most commonly

observed skin-related AEs were

photosensitivity reactions (observed in 12.2%

of pirfenidone-treated patients compared with

1.7% of placebo-treated patients) and rash

(occurring in 32.2% of pirfenidone-treated

compared with 11.5% of placebo-treated

patients). Events were mild to moderate

in severity (Table 2). Photosensitivity reaction

led to discontinuation in three (0.9%)

pirfenidone-treated patients and one (0.3%)

placebo-treated patient. Rash led to

discontinuation in five (1.4%)

pirfenidone-treated patients and no

placebo-treated patients [15]. An example of

photosensitivity on the exposed skin of a

pirfenidone-treated patient is shown in Fig. 2a.

The seasonal variation in frequency of skin

reactions in the CAPACITY studies suggests an

association with high-intensity sunlight

exposure (Fig. 1b). Laboratory studies have

suggested that the underlying mechanism of

pirfenidone in photosensitivity reactions is

likely to be phototoxic and related to the

drug’s ability to absorb both ultraviolet (UV) B

and UVA (Fig. 1c) [30]. Absorption of UV light

by pirfenidone in skin tissue could result in skin

lesions due to the generation of reactive oxygen

species and lipid peroxidation, as both occur

in vitro at physiologically relevant

concentrations [30]. Although no wavelength

dependency studies have been conducted in

humans, preclinical guinea pig findings support

the hypothesis that pirfenidone-induced skin

reactions are phototoxic, and therefore

proportional to light exposure and drug

concentration [31]. These animal studies also

demonstrate that the use of a sunscreen with a

high protection factor significantly reduces the

severity of skin reactions. Whether the

wavelength dependency extends into the

visible region in man is yet unknown.

Fig. 2 Photosensitivity in pirfenidone-treated patients.a Patient 1: mild photosensitivity after 8 h driving. The patienthad been receiving treatment with pirfenidone for 7 days. Thepatient presented with erythema localized to the morephotoexposed areas of the hands. He had previously followedadvice regarding photoprotection. On the day in question, heused a broad-spectrum SPF50? sunscreen in the morningbefore sun exposure, but did not repeat the application.b Patient 2: moderate photosensitivity after 14 days pirfenidonetreatment. The patient presented with erythema and peeling,mainly on the hands and face. Patient had omitted to applysunscreen protection. c Patient 2: the same patient improvedfollowing 7 days of topical treatment (silver sulfadiazine),sunscreen protection, and pirfenidone dose reduction. Thepatients and treating physicians provided permission for the useof these images. SPF sun protection factor

382 Adv Ther (2014) 31:375–391

RECOMMENDATIONS FOR THEPREVENTION AND MANAGEMENTOF PIRFENIDONE-RELATED AES

Treatment management should be deployed in

centers with appropriate expertise and

experience in the management of IPF. The

recommended daily dose of pirfenidone in

Europe for adult patients with IPF is three

267 mg capsules three times a day with food

(preferably at the end rather than the beginning

of themeal) for a totalof2,403 mg/day [23].Upon

initiating treatment, the dose is titrated over a

14-day period to the recommended daily dose of

nine capsules (2,403 mg) per day: first week, one

capsule (267 mg) three times a day; second week,

two capsules (534 mg) three times a day; third

week onwards, full dose of three capsules

(801 mg) three times a day [23]. It is

recommended that pirfenidone is taken with

food, typically during or after a meal in order to

prevent drug-related AEs [23]. Generally, a

stepwise clinical approach as described in Fig. 3

can be adopted to manage pirfenidone-related

GI and skin-related AEs.

The following sections report

recommendations on additional measures that

may be adopted in daily practice for the

prevention and management of GI and

skin-related AEs, based on the summary of

product characteristics (SmPC) and

complemented by our opinion and

observations from clinical experience. It

should be noted that decisions regarding

treatment, particularly re-introduction

following discontinuation due to AEs, should

always be made in conjunction with the

patient, who should be made fully aware of

potential drug side-effects. Both parties should

consider the balance between quality of life and

efficacy benefits of continued treatment in

order make informed decisions on disease

management.

Gastrointestinal Adverse Events

In addition to current recommendations to take

pirfenidone during or after a meal [23], we

suggest further practical considerations in

patients experiencing tolerability challenges

from GI AEs, such as taking each of the three

capsules separately throughout the meal, rather

than simultaneously. If the meal consists of

several courses, each capsule could be taken

between courses. In support for this

recommendation, preclinical studies have

shown that splitting pirfenidone doses

partially alleviates pirfenidone’s inhibitory

effect on gastric motility in animal models

(InterMune data on file). This is further

supported by a real-world study in which

patients were encouraged to take pirfenidone

at the start, middle, and end of a meal to help

minimize side-effects [32].

To further improve pirfenidone’s tolerability,

we suggest that a longer initial dosing titration

scheme—for example, starting with one capsule

three times a day and titrating up to the full

dose (three capsules three times a day) over a

period of 4 weeks instead of 2 weeks—may beFig. 3 Stepwise approach to the prevention andmanagement of pirfenidone-related AEs. AE adverse event

Adv Ther (2014) 31:375–391 383

employed. This approach is currently under

investigation in a clinical setting

(Clincialtrials.gov #NCT01933334) [33].

Dose Reduction

If pirfenidone-related AEs are not tolerable, dose

reductions may be helpful, as the incidence of

GI and skin-related AEs with pirfenidone

treatment appear to be dose dependent as

shown in animal models [34]. Depending on

the nature and severity of the AE, we suggest

that the pirfenidone dose may be reduced to 1

or 2 capsules (267–534 mg), 2–3 times a day

with food, with re-escalation to the

recommended daily dose as tolerated. In

support of this suggestion, preclinical studies

have shown that pirfenidone reduces gastric

emptying and small intestinal transit rates in a

dose-dependent manner [29].

If dose reduction is required, we suggest to

first reduce the dose corresponding to the time

of the day when AEs are the most pronounced.

For example, if nausea is experienced in the

morning, delaying or reducing the morning

dose to one or two capsules, may help mitigate

GI symptoms. Dietary and cultural habits

should be taken into account when advising

patients.

Temporary Dose Interruption and

Re-challenging

If AEs still persist despite dose reduction,

temporary treatment discontinuation until

symptoms become tolerable (typically

1–2 weeks) should be considered. Once

symptoms have resolved or become tolerable,

pirfenidone may be re-introduced. In some

treatment centers, a slower re-escalation

scheme (i.e., longer than the usual 2 weeks)

after temporary treatment interruption has

been employed.

Prokinetic Medication

Use of prokinetic agents such as domperidone,

mosapride, and metoclopramide may help

mitigate treatment-related GI AEs [35]. Indeed,

animal studies have shown that prokinetic

agents such as mosapride reduce pirfenidone’s

inhibitory effects on gastric emptying and

intestinal transit rates [29]. Metoclopramide

(for a maximum of 5 days) and domperidone

(no restriction on length of use) are both dosed

at 10 mg three times a day. Use of proton pump

inhibitors may also be helpful for managing GI

side-effects in pirfenidone-treated patients with

IPF [36].

Skin-Related Adverse Events

Preclinical studies have shown that

pirfenidone-induced photosensitivity reactions

reflect the drug’s pharmacokinetic profile and

are proportional to sunlight exposure,

decreasing with the use of higher sun

protection factor (SPF) sunscreens. Therefore,

sun exposure should be avoided for a few hours

following pirfenidone intake, to allow the

drug’s plasma concentration to decrease.

Animal studies have suggested that the extent

of phototoxicity is linked to pirfenidone’s

plasma concentration (InterMune data on file).

The standard approach for preventing and

managing skin AEs as recommended in the

SmPC [23] includes avoiding exposure to direct

sunlight (including sunlamps), use of sunscreen

active against both UVA and UVB, use of

protective clothing, and avoidance of other

medicinal products known to cause

photosensitivity. We expand on this guidance

by suggesting: behavioral avoidance of indirect

(in addition to direct) sunlight, as well

as intense artificial light sources (such as

energy-saving fluorescent lamps); wearing of

384 Adv Ther (2014) 31:375–391

Tab

le3

Sum

mar

yof

reco

mm

enda

tion

sfo

rth

epr

even

tion

and

man

agem

ent

ofpi

rfen

idon

e-re

late

dA

Es

Gen

eral

appr

oach

esto

prev

enti

ngan

dm

anag

ing

pirf

enid

one-

rela

ted

AE

s

Pirf

enid

one

adm

inist

ratio

nan

ddo

sem

odifi

catio

ns

Pirf

enid

one

caps

ules

(267

mg)

shou

ldbe

take

nin

divi

dual

ly,o

ver

the

cour

seof

am

eal:

fine

tuni

ngsh

ould

take

into

acco

unt

cultu

ral

diet

ary

habi

ts

Ifna

usea

isex

peri

ence

din

the

mor

ning

,the

mor

ning

dose

may

bede

laye

dor

redu

ced

Am

axim

umof

thre

eca

psul

es(8

01m

g)sh

ould

beta

ken

wit

hth

em

ain

mea

lof

the

day,

whi

lefe

wer

[1or

2ca

psul

es(2

67–5

34m

g)]

may

beta

ken

wit

hlig

hter

mea

ls

Upo

ntr

eatm

ent

init

iati

on,t

heup

-tit

rati

onsc

hem

eca

nbe

exte

nded

to4

wee

ksun

til

the

daily

reco

mm

ende

ddo

seis

reac

hed

Tem

pora

rytr

eatm

ent

inte

rrup

tion

ssh

ould

beco

nsid

ered

ifsy

mpt

oms

dono

tre

solv

efo

llow

ing

dose

redu

ctio

n

Follo

win

gdo

sein

terr

upti

on,p

irfe

nido

neco

uld

bere

-intr

oduc

edw

ith

aslo

wer

re-e

scal

atio

nsc

hem

eto

the

full

dose

All

trea

tmen

t-re

late

dde

cisi

ons

shou

ldbe

mad

efo

llow

ing

disc

ussi

onw

ith

the

pati

ent

and

wit

hth

eai

mof

bala

ncin

gqu

alit

yof

life

and

effic

acy

bene

fits

Add

itio

nal

mea

sure

sto

man

age

GI

AE

s

Prok

inet

icag

ents

may

help

mit

igat

eG

IA

Es

Add

itio

nal

mea

sure

sto

prev

enti

onan

dm

anag

esk

inA

Es

Prev

entio

nof

phot

osen

sitiv

ityre

actio

ns

Cha

nge

beha

vior

toav

oid

sun

expo

sure

:

•Se

ekto

avoi

dsu

nex

posu

reas

muc

has

poss

ible

,esp

ecia

llyat

mid

-day

,in

the

late

afte

rnoo

n,an

ddu

ring

seas

onal

high

UV

peri

ods.

Rem

embe

rth

atth

esu

n’s

UV

Aco

mpo

nent

can

pene

trat

ecl

ouds

,clo

thin

g,an

dca

rw

indo

ws

•A

void

sun

expo

sure

for

afe

who

urs

afte

rth

em

eal

atw

hich

pirf

enid

one

was

adm

inis

tere

d

Prot

ect

skin

from

the

sun

wit

hap

prop

riat

ecl

othi

ng:

use

ofw

ide-

brim

med

hats

,sun

glas

ses,

long

-sle

eve

shir

ts,a

ndtr

ouse

rsis

reco

mm

ende

d,as

are

glov

esfo

r

driv

ing

and

outd

oor

acti

viti

es

Prot

ect

skin

from

the

sun

wit

hsu

nscr

een:

freq

uent

and

thor

ough

appl

icat

ion

ofa

broa

d-sp

ectr

umSP

F50

suns

cree

nw

ith

both

UV

Aan

dU

VB

prot

ecti

onis

man

dato

ry

Man

agem

ent

ofsk

inra

shes

Inca

seof

rash

es,p

irfe

nido

nedo

sesh

ould

bere

duce

d.If

rash

esst

illpe

rsis

taf

ter

7da

ys,p

irfe

nido

neth

erap

ysh

ould

bedi

scon

tinu

edfo

r15

days

and

may

be

slow

lyre

-intr

oduc

edon

cesy

mpt

oms

have

reso

lved

Ifra

shes

are

due

toan

alle

rgic

reac

tion

,pir

feni

done

ther

apy

shou

ldbe

perm

anen

tlydi

scon

tinu

ed

Adv Ther (2014) 31:375–391 385

thick-weave clothing, use of a broad-brimmed

hat, and, when necessary, gloves.

To further illustrate the above guidance of

the SmPC, Table 3 details our expert

recommendations to prevent skin

photosensitivity reactions, highlighting the

importance of behavioral changes and

protection through appropriate clothing and

thorough sunscreen application.

Dose Reduction

In cases of mild to moderate photosensitivity

reaction or rash (i.e., when the vast majority of

burn is superficial—painful erythema and

scaling may be present on exposed areas, but

with no edema, exudation, or blistering) that

does not spontaneously resolve, the dose may

be reduced to one capsule (267 mg) three times

a day for 7 days, or until symptom resolution.

Symptoms are considered to be resolved once

the redness and scaling have disappeared.

Temporary Dose Interruption and

Re-challenging

If a rash persists for more than 7 days despite

pirfenidone dose reduction, therapy should be

discontinued for approximately 15 days. Upon

resolution, pirfenidone may be re-introduced

and re-escalated to the recommended daily

dose, or as tolerated, in the same manner as

the initial regime, or using the slower

re-escalation regime previously described (i.e.,

extended over 4 weeks as opposed to 2 weeks).

Patients experiencing a severe

photosensitivity event (erythema and edema

with exudation, erosions, blistering, cracked or

scarred skin, possible dehydration) of

sun-exposed skin (i.e., a non-allergic reaction),

should be instructed to seek medical advice on

dose adjustments and temporary

discontinuation, until the skin reaction

normalizes. In our collective clinicalTa

ble

3co

ntin

ued

Inca

ses

ofse

vere

phot

osen

siti

vity

reac

tion

s,pi

rfen

idon

esh

ould

bedi

scon

tinu

edan

dre

plac

edw

ith

pred

niso

ne25

mg/

day

for

7–10

days

.Aft

erdi

sapp

eara

nce

of

the

skin

reac

tion

,pir

feni

done

may

bere

-intr

oduc

edfo

llow

ing

ave

ryslo

wre

-esc

alat

ion

Edu

catio

n

Pati

ent

(and

spou

sal)

educ

atio

nsh

ould

beun

dert

aken

atse

vera

lle

vels

(phy

sici

an,n

urse

,and

phar

mac

ist)

and

shou

ldbe

supp

orte

dby

exis

ting

educ

atio

nal

mat

eria

ls(e

.g.,

pati

ent

info

rmat

ion

leafl

et)

Phys

icia

nspl

aya

cent

ral

role

inpa

tien

ted

ucat

ion

and

inpr

ovid

ing

best

advi

ceby

cons

ider

ing

the

pati

ent’s

clin

ical

hist

ory,

pote

ntia

lou

tdoo

roc

cupa

tion

s/

hobb

ies/

spor

t,or

poss

ible

conc

omit

ant

trea

tmen

tw

ith

othe

rph

otos

ensi

tizi

ngdr

ugs

AE

adve

rse

even

t,G

Iga

stro

inte

stin

al,S

PFsu

npr

otec

tion

fact

or,U

Vul

trav

iole

t

386 Adv Ther (2014) 31:375–391

experience, use of topical treatments for burns

(e.g., silver sulfadiazine or potent steroids)

immediately after the appearance of skin

lesions may help attenuate reactions and

improve associated symptoms. An example of

a patient with moderate sensitivity treated with

topical emollients and a reduction in

pirfenidone dose is shown in Fig. 2b, c.

After the skin reaction has cleared,

pirfenidone may be re-introduced with the

slower stepwise re-escalation scheme. If

exposure to sunlight at mid-day is

unavoidable, the pirfenidone dose at

lunchtime could be reduced.

It should be noted that a significant number

of skin-related AEs experienced with

pirfenidone are associated with unprotected

sun exposure. Rashes that appear allergic in

nature (urticarial or occurring on parts of the

body that are not exposed to sunlight) are

uncommon. If such a rash occurs, however,

pirfenidone should be permanently

discontinued, and the use of anti-histamines

and oral prednisone should be considered.

Correct diagnosis of an allergic rash is very

important, as these patients should not be

re-challenged with pirfenidone.

In cases of photosensitivity, the decision

about re-challenging following treatment

interruption must be made according to

clinical judgment based on the type and

severity of the reaction; dermatological advice

can be helpful. Dose interruption can be

avoided if enough emphasis is placed on

prevention methods, as described in Table 3.

Patients should be encouraged to take

photographs of any skin changes to aid

diagnostic evaluation, particularly if

uncertainty exists as to whether a rash has a

phototoxic- or an allergic-type mechanism.

Improving Patient Education

Patient education is a central part of the

management of skin AEs and should include

communication with a patient’s spouse or carer.

Accordingly, physicians, nurses, and

pharmacists play an important role in the

dissemination of patient educational materials

(such as the patient information leaflet [37])

and in emphasizing preventive measures (e.g.,

behavioral, clothing, and sun protective barrier

use). Ideally, physicians and nurses should

dedicate adequate time to educate patients

with respect to preventive measures and

behavioral changes.

As previously described, the importance of

generous and frequent re-application of a high

SPF and high UVA (extending into the visible

region) type of sunscreen should be

emphasized. The use of existing supporting

patient educational materials [37] and simple

educational tools is highly recommended. Some

centers have dedicated nurses and/or specific

home-care programs that play an important

role in this area. Patients should be made aware

that although dense cloud, thick clothing, and

glass may offer some protection against UV

exposure, UVA rays may penetrate such barriers,

which is important with respect to driving.

Prescribing or recommending a broad-spectrum

sunscreen at the same time as pirfenidone may

emphasize the importance of sun protection.

In terms of AE management, the physician

plays a central role by communicating

preventive measures and existing educational

tools to the patient. During patient assessment,

the physician has the opportunity to educate

and provide the best advice to the patient by

considering clinical history (skin phototype and

previous history of photosensitive skin disease

such as lupus erythematosus, polymorphic light

Adv Ther (2014) 31:375–391 387

eruption, etc.), possible outdoor occupations

(e.g., laborer, farmer) or hobbies/sport (e.g.,

golfing, sailing), concomitant treatment with

other photosensitizing drugs (e.g., tetracycline

antibiotics), and the patient’s mental health state

(which can affect motivation and adherence). For

patients who present with photosensitivity

despite significant photoprotection, it is

important to consider the possibility of vitamin

D deficiency. A vitamin D plasma assay should be

considered with administration of oral vitamin D

as appropriate.

The outcomes of efficient patient

communication are highlighted in a real-world

pirfenidone study of 40 patients with IPF [32].

During the first 6 months of this study six

patients (15%) discontinued treatment due to

AEs. In the latter 10 months, however, there were

no discontinuations. The authors of this study

[32] attribute this to a number of factors,

including a monthly specialist nurse review (for

the first 3 months of treatment) to assess and

reinforce AE avoidance measures. Patients were

also given a contact number and encouraged to

speak with a specialist nurse if they experienced

any AEs; this ensured that appropriate measures

such as dose reduction, temporary

discontinuation, and/or additional treatment of

side-effects could be enforced without delay in

order to rapidly alleviate AEs [32]. This real-world

study suggests that simple patient education and

communication measures can substantially

increase treatment adherence and compliance,

which enables patients with IPF to benefit from

the decreased disease progression observed with

continued pirfenidone treatment.

CONCLUSION

Data from clinical trials show the clinically

meaningful benefit and favorable safety profile

of pirfenidone. While dose reduction can

improve AE tolerability by mitigating AE

occurrence/severity, better management of AEs

will lead to optimized care and allow patients to

benefit from the potential effectiveness of

pirfenidone. To prevent and manage GI and

skin-related AEs more effectively, further

research is required to understand the effect of

pirfenidone on gastric motility and

photosensitivity reactions. Our opinions

regarding the prevention and management of

pirfenidone-related AEs in clinical practice are

summarized in Table 3. These should be

regarded as a complement to the available and

published information on pirfenidone.

ACKNOWLEDGMENTS

This manuscript is based on discussions

between authors at a clinical advisory board

which was supported by a grant from

InterMune International AG, Basel,

Switzerland. The authors thank Dominique

Spirig, formerly of Fishawack Communications

GmbH, Basel, Switzerland, Neil Burton of

Fishawack Communications GmbH, and

Roisın O’Connor from inScience

Communications, Springer Healthcare Ltd.,

London, UK, for medical writing and editorial

assistance, which was funded by InterMune

International AG. The authors also thank

Christophe Giot (InterMune International AG,

Basel, Switzerland) for his contribution to the

discussion of pirfenidone clinical trial data, and

Lin Pan and Scott Seiwert (InterMune Ltd.,

Brisbane, USA) for their contribution to the

discussion of pirfenidone preclinical data. All

named authors met the ICMJE criteria for

authorship for this manuscript, take

responsibility for the integrity of the work as a

whole, and have given final approval for the

388 Adv Ther (2014) 31:375–391

version to be published. All authors had full

access to all of the data in this study and take

complete responsibility for the integrity of the

data and accuracy of the data analysis.

Conflict of interest. UC has received

consultancy fees, speaker fees and research grants

from InterMune Inc. and Boehringer Ingelheim,

consultancy fees from Gilead, Roche, Bayer

Centocor, and speaker fees from Zambon. EB has

received research grants and speaker fees from

InterMune Inc, and is an investigator in

the PASSPORT and PANORAMA (EudraCT:

#2012-000564-14) studies. VC has participated as

a consultant, speaker and investigator for

Actelion, Boehringer Ingelheim, Gilead,

InterMune Inc. and Roche. PD, JJE, JF, RG and

PMH have no conflicts of interest to disclose. MK

has received an unrestricted academic grant from

InterMune Inc., and consulting and speaker’s fees

from InterMune Inc. and Boehringer Ingelheim.

TMM is in receipt of unrestricted academic grants

from GlaxoSmithKline and Novartis. In the last

3 years, TMM (or his institution) has received

advisory board or consultancy fees from

Boehringer Ingelheim, GlaxoSmithKline,

InterMune Inc, Novartis, Lanthio Pharma,

Takeda, Sanofi-Aventis and UCB. He has received

speaker’s fees from UCB, Boehringer Ingelheim,

InterMune Inc. and AstraZeneca and participated

as an investigator in industry sponsored clinical

trials run by Boehringer Ingelheim,

GlaxoSmithKline, InterMune Inc., Novartis,

Roche and Celgene; his institute has received

educational grant support from InterMune Inc.

MMM has participated as a consultant and speaker

for InterMune Inc., Actelion and Esteve-Teijin,

and has participated in clinical trials sponsored by

Sanofi, Roche, Boehringer Ingelheim and

InterMune Inc. KN and AS have no conflicts of

interest to disclose. CV has received research

grants and consulting and speaker fees from

InterMune Inc., and is an investigator in the

PASSPORT and PANORAMA studies.

Compliance with ethics guidelines. The

analysis in this article is based on previously

conducted studies, and does not involve any

new studies of human or animal subjects

performed by any of the authors. The patients

and treating physicians provided permission for

the use of the images in Fig. 2.

Open Access. This article is distributed

under the terms of the Creative Commons

Attribution Noncommercial License which

permits any noncommercial use, distribution,

and reproduction in any medium, provided

the original author(s) and the source are

credited.

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